US Pharm. 2015;40(2)27-30.
In the last few years, there has been increasing attention on the association between subclinical hypothyroidism (SCH) and cardiovascular disease. Prospective data have shown an increased risk of coronary heart disease (CHD) events, heart failure, and cardiovascular mortality among adults affected with this condition.1 However, data regarding the association between SCH and cardiovascular disease outcomes are conflicting among large prospective cohort studies, possibly reflecting the differences in participants’ age, sex, and thyroid-stimulating hormone (TSH) levels, or the presence of preexisting cardiovascular disease.2 At this point, uncertainty still remains as to how best to treat these patients because extensive research has never been done to address the safety and efficacy of thyroid hormone supplementation in SCH in older adults.3
This article will address the underlying molecular pathways attributed to the cardiovascular events induced by factors associated with SCH, and also report on the large multicenter, randomized, controlled trial (RCT) currently under way to address the aforementioned question regarding treatment as it relates to risk, benefit, and quality of life in older adults.
Thyroid disorders occur over the entire age spectrum; however, many appear to be increasingly common with advancing age.4 SCH, a common disorder that increases with age, is defined as elevated TSH levels with normal levels of free thyroxine (FT4).5 It denotes a decline in thyroid activity, with triiodothyronine (T3) also found to be in the normal range. SCH (TABLE 1) may vary from being asymptomatic to having mild nonspecific symptoms without clear signs and symptoms of hypothyroidism, such as decreased FT4.6 This condition affects up to 18% of the elderly, with a prevalence that is higher in women than in men.1 A variety of factors influence this condition, including age, gender, race, body mass index, and dietary iodine intake. Further complicating the picture, the boundary point of serum TSH used for the diagnosis of SCH is inconsistent among studies.7 Of note, controversy exists regarding the limits of the TSH reference range.8 For example, while serum TSH is known to increase with age, it may not be associated with mortality and may even be associated with longevity; evidence suggests that those >80 years of age may actually enjoy a protective benefit, with reduced risk of cardiovascular and overall mortality found in patients aged 85 years.1,9-11
Patients with SCH are at risk for progression to overt thyroid dysfunction, with an increased risk in these subgroups: females, individuals with higher levels of TSH, and persons with antithyroid peroxidase antibodies (caveat: those without antithyroid peroxidase antibodies also have a higher risk of progression).12 Spontaneous recovery from SCH can occur, and the likelihood is higher with TSH levels <10 mIU/L.13
SCH and Cardiovascular Disease Events: Basic Research
According to Lu et al, it has been observed that SCH predisposes patients to endothelial dysfunction (ED), an early sign of athero-sclerosis, partially explained by the following factors14:
• Low-grade chronic inflammation factors
• Oxidant stress
• Insulin resistance
The above factors affect specific molecular pathways in endothelial cells and cause elevated levels of nitric oxide and other molecular changes that are characteristic of ED. ED then leads to14:
• Impaired vascular tone
• Platelet aggregation and thrombosis
• Leukocyte adhesion and infiltration
• Smooth muscle cell proliferation
Ultimately, these physiological circumstances may contribute to atherosclerotic lesion formation and cardiovascular disease events.14 Researchers have noted that SCH may be a risk factor for cardiovascular events related to arterial stiffening and left ventricular diastolic dysfunction.15 Furthermore, patients with acute or chronic nonthyroid disorders may have abnormal thyroid function tests. Euthyroid sick syndrome (ESS) is characterized by low serum levels of thyroid hormones—most commonly decreased T3—in clinically euthyroid patients with normal TSH levels and nonthyroid systemic illness (e.g., myocardial infarction [MI], chronic renal failure, diabetic ketoacidosis, sepsis). Of note, sudden cardiac death may be influenced by SCH and ESS in the short term; given the physiological association of thyroid dysfunction in relation to chronic kidney disease, regular assessment of thyroid status may help estimate cardiac risk in dialysis patients.16,17
Lu et al further indicate that while levothyroxine replacement therapy appears to improve the aspects of SCH mentioned previously (i.e., recovery of endothelial cells from early-stage injury in the majority of cases) and early intervention can slow down the progress of atherosclerosis, particularly in the severe SCH (TSH 10 mIU/L) group, levothyroxine replacement therapy would also increase the risk of osteopenia and atrial fibrillation; therefore, certain controversies remain, particularly for the elderly.14,18 Moreover, the influence of thyroid hormones on cardiac remodeling has not been thoroughly investigated at the molecular and cellular levels.19 Thus, more study data are required to confirm the benefit of levothyroxine therapy for patients with SCH.14
The TRUST Project
The TRUST Thyroid Trial (Thyroid hormone Replacement for Untreated older adults with Subclinical hypothyroidism: a randomized placebo-controlled Trial) aims to resolve uncertainties regarding the risks and benefits of treatment on relevant clinical outcomes in elderly persons with SCH.2,3 It has been noted to be the first adequately equipped RCT to address this objective.1 This RCT is a multicenter study conducted in four European countries including Switzerland, Scotland, Ireland and the Netherlands; it examines thyroid hormone replacement therapy versus placebo in elderly individuals with persisting SCH (Clinical Trials.gov NCT01660126). To ensure good generalizability of the trial results and to allow direct conclusions for a general practitioner’s clinical decisions, the study involves a broad population of community-dwelling individuals aged 65 years with persistent subclinical hypothyroidism, defined as a TSH level 4.6 to 19.9 mIU/L measured on two or more occasions at least 3 months apart with normal FT4 levels.
Exclusion criteria were defined as: 1) patients on thyroid-altering medication; 2) recent thyroid surgery or radio-iodine therapy within the last year; 3) grade IV heart failure according to the New York Heart Association Functional Classification; 4) recent hospitalization for major illness, in order to exclude patients with ESS, 5) a prior clinical diagnosis of dementia; and 6) acute coronary syndrome within the last 4 weeks. Study participants are randomized to either placebo or levothyroxine with a starting dose of 50 mcg daily (25 mcg in patients with a weight <50 kg or a history of CHD) and with subsequent dose adjustments according to the serum TSH level. These individuals are followed for 1 to 4 years. The primary outcomes include fatal and non-fatal cardiovascular events and disease-specific quality of life; secondary outcomes are muscle strength, blood pressure, cognitive function, functional capacity, general quality of life, and mortality.
The Institute for Evidence-based Medicine in Old Age (IEMO), an organization that aims to improve healthcare in the elderly by generating evidence for their treatment, has joined the TRUST Thyroid Trial with its parallel study called the IEMO 80+ Thyroid Trial (450 community-dwelling participants >80 years of age in the Netherlands).20 The TRUST Project, a collaboration between the TRUST Thyroid Trial and IEMO 80+ Thyroid Trial, is under way. Both trials use identical research infrastructures and share local procedures; observing the effects on the participants of both studies allows for providing specific advice regarding the treatment of SCH in the population >80 years of age. The research of The TRUST Project collaboration is organized and funded by the European Union. Experts in aging, thyroid conditions, and vascular disease from around Europe work together in The TRUST Project, further collaborating with thyroid experts from the University of California in the United States. 21
The two studies have one research question: What is the safety and efficacy of thyroid hormone supplementation in older adults with SCH? According to the study website, both trials started recruiting participants in 2013, and researchers project that they will follow the study participants over a 5-year period.20 It is expected that this collaboration will report by late 2016 and will provide data that properly inform future evidence-based guidelines.21
Recommendations for screening vary widely among experts and across different medical associations (see Resource).22 Uniform national guidelines for screening for thyroid disease with serum TSH levels have not been established. Prior to a recommendation to routinely screen the general population, large-scale RCTs are required to confirm that levothyroxine therapy will improve quality of life in otherwise healthy individuals with the mildly elevated TSH level (5-10 mIU/L) that is typical of most patients with SCH.9
To Treat or Not to Treat? Individualized Therapy
Thyroid hormones have known effects on heart rate and cardiac excitability. Hajje et al indicate that in animal studies, hypothyroidism is related to cardiac function decline, fibrosis, and inflammation; and most important, the rapid correction of hypothyroidism has led to cardiac injuries. These results might offer new insights for the management of hypothyroidism-induced heart disease.19 In light of the current lack of evidence regarding the optimal treatment strategy in patients with SCH, Baumgartner et al suggest that the best management to date is inclusion in ongoing trials (see Resource).1 However, for individuals who cannot be included in a trial, these researchers do not recommend initiating treatment in patients with TSH levels <10 mIU/L, but rather, recommend following serum TSH values.1,8 It has also been suggested that if TSH levels exceed 10 mIU/L, levothyroxine supplementation might be considered; but even in these individuals, there is no direct evidence from RCTs justifying treatment. 23
Consensus will require more large-scale RCTs that are government-sponsored and multicentered, involving various age groups and multiple morbidities, especially in developing countries, to assess the efficacy of levothyroxine therapy for SCH and the specific subgroups (e.g., TSH <10 mIU/L, TSH >10mIU/L).1,6,14 The arguments against levothyroxine therapy include cost and the possibility of unintentional overtreatment, with the ensuing risks of reduced bone mineral density and atrial fibrillation; other cardiovascular adverse effects include angina, cardiac arrest, heart failure, hypertension, MI, palpitations, increased pulse, and tachycardia.24 Meanwhile, when levothyroxine therapy is considered, it should be deemed a therapeutic trial; if no benefit is perceived, it can be discontinued.25 Individualized therapy is key, taking into account patient preference (i.e., a patient-centered approach), presence of symptoms, age, and associated medical conditions.26
Despite their ever-increasing consumption of healthcare, the elderly, who are becoming a more conspicuous segment of modern Western societies, are systematically excluded from the studies that guide clinicians in their treatment. Owing to the controversies and current lack of consensus regarding whether to treat SCH, which is associated with cardiovascular disease events, The TRUST Project—TRUST Thyroid Trial and IEMO 80+ Thyroid Trial—is a welcome collaboration that is expected to provide much-needed guidance specific to older adults with this common thyroid condition.
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3. The TRUST Thyroid Trial. www.trustthyroidtrial.com. Accessed January 21, 2015.
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20. IEMO: Collaboration TRUST and IEMO 80+. www.trustthyroidtrial.com/index.cfm?p=6BB48CA6-9B39-5C24-D58B941E7A8E6CFC. Accessed January 21, 2015.
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24. Semla TP, Beizer JL, Higbee MD. Geriatric Dosage Handbook. 19th ed. Hudson, OH: Lexicomp; 2014:781-784.
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